Broadening bipolar diagnostic criteria: why not start with hypomania?

Strakowski et al have done an outstanding job in discussing the benefits and risks of broadening the diagnostic criteria for bipolar disorder. They note that advantages are more accurate diagnosis and more appropriate treatment of those with bipolar disorder, while disadvantages are overdiagnosis and exposure to ineffective medications with deleterious side effects of those without the illness, as well as impediment of scientific discovery. In support of broadened criteria, they cite evidence that bipolar I disorder is on a spectrum with major depressive disorder (MDD) via bipolar II disorder, and with schizophrenia via schizoaffective disorder. This includes response of antidepressant-resistant MDD to lithium; common genetic findings between bipolar disorder and MDD and between bipolar disorder and schizophrenia; and the response of all three conditions to second generation antipsychotics (SGAs). More evidence, however, is given against broadening bipolar diagnostic criteria, including recent findings from a large study by Perlis et al 1 that measures of bipolar spectrum disorder among patients with MDD did not predict antidepressant treatment response, and findings of neurocognitive and neuroimaging differences between patients with bipolar I and II disorder. They conclude that it is premature to advance a new bipolar diagnostic schema, arguing that extant nosologies are already likely compromised by a heterogeneous collection of etiologies. A spectrum may be defined as a range of linked conditions such that there is not a unitary disorder but rather a syndrome composed of subgroups. That there are differences between bipolar I and bipolar II disorder, or between bipolar II disorder and MDD, does not argue against a spectrum construct, especially since the disorders are thought to represent complex genetic illnesses. Indeed, the first published cross-disorder genome wide association study of bipolar disorder, MDD, and schizophrenia has revealed a chromosomal region having effects specific to bipolar II disorder, as well as several chromosomal regions having pleiotropic effects influencing all three diagnostic classes 2. Such a finding lends support to the bipolar spectrum concept by inferring specific as well as shared genetic liabilities across the member disorders. A number of diagnostic criteria for a bipolar spectrum have been proposed 3,4. Some of these models include forms that lack mania or hypomania but have other indicators of bipolarity, such as early onset of depression, highly recurrent depressive episodes, and/or family history of bipolar disorder. As noted by Strakowski et al, a large study of patients with MDD by Perlis et al 1 did not support such a broad construct when using antidepressant response as the validating variable. Growing epidemiological and prospective data, however, indicate that subthreshold hypomanic symptoms are common and of nosological relevance, lending support to narrower bipolar spectrum models. Angst et al 5 found that nearly 40% of study participants in the National Comorbidity Survey Replication with MDD had a history of subthreshold hypomania, defined as the presence of at least 1 of the 2 screening questions for mania but failure to meet full diagnostic criteria for mania. According to these questions, hypomanic symptoms had to last several days or longer. Individuals with MDD and subthreshold hypomania had an earlier age of onset, more episodes of depression, and higher rates of comorbidity than these without hypomania, but lower levels of clinical severity than those with bipolar II disorder. That the differences among the three categories were graded could be taken as further support of an underlying spectrum. Fiedorowic et al 6 followed 550 individuals in the National Institute of Mental Health (NIMH) Collaborative Depression Study with MDD at intake for a mean of 17.5 years and up to 31 years. On survival analysis, 20% of the sample experienced hypomania or mania, and conversion to a bipolar diagnosis. Number of subthreshold hypomanic symptoms (3 of 5 was the optimal cut off) was associated with subsequent onset of hypomania or mania independent of other risk factors. Studies of subthreshold hypomania might be important to the understanding of antidepressant-associated switch, about which much controversy exists, and other treatment questions. In a study of 176 bipolar patients participating in 10-week adjunctive antidepressant treatment trials, 46 experienced treatment-emergent mania or hypomania 7. The only difference between the group that switched and the group that did not was a small but significantly higher Young Mania Rating Scale score (i.e., sub-threshold hypomanic symptoms) before antidepressant exposure. As patients with bipolar II depression have been shown to be less likely to switch with antidepressants than those with bipolar I depression 8, there may be a spectrum of liability for the anti-depressant-induced switch process that is highest for bipolar I disorder, lowest for MDD, and intermediate for bipolar II disorder. It may also be that antidepressants are more likely to trigger subthreshold hypomania than threshold hypomania or mania, and that in MDD inadequately responsive to an antidepressant, subthreshold hypomania (spontaneous or antidepressant-related) might predict better response to augmentation with lithium or a SGA rather than with a second antidepressant. These hypotheses can be empirically tested with operationally-defined diagnostic criteria for subthreshold hypomania and interviews to evaluate them 9. In light of well-founded concerns about prematurely broadening bipolar diagnostic schema, provisional criteria for subthreshold hypomania could be provided for further study in DSM-5 or ICD-11 (e.g., in an appendix). Examples could be the DSM-IV or ICD-10 definitions of hypomania except for a symptom duration of 1-3 days, or definitions focusing on behavioral overactivity, but there are others 9. A definition of subthresh-old hypomania, in turn, would allow identification of specific subtypes of bipolar disorder not otherwise specified (e.g., bipolar III disorder or MDD with subthreshold hypomania), provisional criteria for which could also be provided. Identifying discrete disease entities along dimensions of continuous variation is an important goal of medical classification, and phenotypic refinement needs to advance hand-in-hand with findings in neuroscience, genetics, and treatment response 10. Subthreshold hypomanic symptoms are a public health problem, and identifying the border of hypomania with depression, other conditions characterized by hypomanic symptoms (e.g., impulse control disorders), and mental health has emerged as an important public health need. Criteria sets for subthreshold hypomania provided for further study in the DSM-5 or ICD-11 could help further delineate the boundaries of hypomania, and thus the bipolar spectrum, in an empirical manner without prematurely broadening bipolar disorder diagnostic criteria.